Douglas N. Ishii, PhD
Office: 245 Physiology Building
Research Interests -- Molecular Neurobiology; Neurotrophic Factors; Diabetic Neuropathy; Brain Atrophy and Dementia
We are interested in the neurobiology of the neurotrophic insulin-like growth factor (IGF) hormones, as well as their capacity to treat various neurological diseases and disorders. This laboratory discovered that IGFs are circulating neurotrophic factors. The highest levels of IGF-II gene expression are in brain, spinal cord, and nerves , and its expression in perinatal muscle correlates closely with synaptogenesis in rats . Neurite (axon or dendrite) outgrowth and the survival of neurons in culture are supported by IGFs. Following nerve crush, infusion of IGFs increase, whereas anti-IGF antibodies decrease the rate of sciatic nerve regeneration in rats . IGF-I mRNAs are increased all along the nerve distal to crush, whereas IGF-II mRNAs are increased mostly at the end of nerves and in denervated muscle. Disconnection of nerves from muscle results in motoneuron death in neonatal rats. Such motoneuron death is prevented by IGF-II, whereas exacerbated by anti-IGF antibodies . Others have shown that transgenic mice over-expressing IGF-I have brains 55% larger than normal.
Nearly 16 million Americans have diabetes, and approximately 15-20% have symptomatic neuropathy including unrelenting pain, bladder dysfunction, impotence, muscle weakness, and gastroparesis. More than 80,000 diabetic limb amputations are performed each year. A new theory proposes that abnormally low IGF activity in diabetes may be pathogenic for neuropathy . Diabetic rats have reduced IGF gene expression in liver, spinal cord, nerves and brain; replacement treatment with IGFs prevents neuropathy, despite unabated hyperglycemia . Diabetic patients have reduced circulating IGF levels, and those with neuropathy have lower levels than those without. Taken together, these studies suggest that IGF treatment may prevent or reverse neuropathy in diabetic patients, and clinical trials are urgently needed.
IGFs are proteins, and proteins are widely regarded as incapable
of crossing the blood-CNS-barrier (B-CNS-B). 6OH-DA was injected into
CSF at the cisterna magna in rats. This lesions the noradrenergic
axons that descend from the brainstem down the spinal cord, causing
loss of the hind-limb withdrawal reflex. IGF was subsequently administered
subcutaneously; the IGF crossed the B-CNS-B and prevented loss of
the noradrenergic spinal cord axons as well as retained 40% of the
withdrawal reflex . IGFs were shown to be taken up from the circulation
into CSF , suggesting that circulating IGFs may normally support
the CNS. These data suggest further that the risk associated with
drilling an access hole through the skull to treat patients with neurological
diseases and disorders might be avoided by s.c. or i.v. IGF administration.
Current studies show that s.c. IGF treatment can prevent cognitive
disorder associated with brain atrophy in rats , and such treatment
might prevent dementia in clinical conditions such as Alzheimer's
 Soares MB, Urken A, Ishii DN, Mills L, Episkopou V, Cotter S, Zeitlin S, Efstratiadis A. 1986. Rat insulin-like growth factor II gene: A single gene with two promoters expressing a multitranscript family. J Molec Biol 192:737-752.
 Ishii DN. 1989. Relationship of IGF-II gene expression in muscle to synaptogenesis. Proc Natl Acad Sci USA 86:2898-2902.
 Near SL, Whalen LR, Miller JA, Ishii DN. 1992. Insulin-like growth factor-II stimulates motor nerve regeneration. Proc Natl Acad Sci USA 89:11716-11720.
 Pu S-F, Zhuang H-X, Marsh DJ, Ishii DN. 1999. Insulin-like growth factor-II increases and IGF is required for spinal motoneuron survival following sciatic nerve axotomy. J Neurosci Res 55:9-16.
 Ishii DN. 1995. Implications of IGFs in pathogenesis of diabetic neuropathy. Brain Res Rev 20:47-67.
 Zhuang H-X, Wuarin L, Fei Z-J, Ishii DN. 1997. Insulin-like growth factor (IGF) gene expression is reduced in neural tissues and liver from rats with non-insulin-dependent diabetes mellitus, and IGF treatment ameliorates diabetic neuropathy. J Pharmacol Exp Therapy 283:366-374.
 Pulford BE, Whalen LR, Ishii DN. 1999. Peripherally administered IGF-I preserves hindlimb reflex and spinal cord noradrenergic circuitry following a central nervous system lesion in rats. Exp Neurol 159:114-123.
 Pulford BE, Ishii DN. 2001. Uptake of circulating insulin-like growth factors (IGFs) into cerebrospinal fluid appears to be independent of the IGF receptors as well as IGF binding proteins. Endocrinology 142:213-220.
 Lupien SB, Bluhm EJ, Ishii DN. 2003. Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult ats. J Neurosci Res 74:512-523.